The clinical management of hyperglycemia in pregnancy complicated by maturity-onset diabetes of the young

Bacon, Siobhán; Schmid, Jasmin; McCarthy, Ailbhe; Edwards, J.R.G.; Fleming, Aileen; Kinsley, Brendan; Firth, Richard; Byrne, B; Gavin, Claire; Byrne, Maria

doi:10.1016/j.ajog.2015.04.037

Cited by 41 publications

(51 citation statements)

References 27 publications

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“…48–54 Modern preconception care, which aims to control hyperglycemia, has failed to prevent the higher incidence of adverse pregnancy outcomes in diabetic pregnancies, compared with the general population. 55,56 Therefore, therapeutics that can prevent diabetes-induced birth defects are needed. Antioxidants are effective in preventing adverse pregnancy outcomes associated with maternal diabetes in animal models 8–10,12–15,17,20–22,36,37 ; however, their effects on human pregnancies are controversial.…”

Section: Commentmentioning

confidence: 99%

Type 2 diabetes mellitus induces congenital heart defects in murine embryos by increasing oxidative stress, endoplasmic reticulum stress, and apoptosis

Reece

Zhong

et al. 2016

American Journal of Obstetrics and Gynecology

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BACKGROUND Maternal type 1 and 2 diabetes mellitus are strongly associated with high rates of severe structural birth defects, including congenital heart defects. Studies in type 1 diabetic embryopathy animal models have demonstrated that cellular stress-induced apoptosis mediates the teratogenicity of maternal diabetes leading to congenital heart defect formation. However, the mechanisms underlying maternal type 2 diabetes mellitus–induced congenital heart defects remain largely unknown. OBJECTIVE We aim to determine whether oxidative stress, endoplasmic reticulum stress, and excessive apoptosis are the intracellular molecular mechanisms underlying maternal type 2 diabetes mellitus–induced congenital heart defects. STUDY DESIGN A mouse model of maternal type 2 diabetes mellitus was established by feeding female mice a high-fat diet (60% fat). After 15 weeks on the high-fat diet, the mice showed characteristics of maternal type 2 diabetes mellitus. Control dams were either fed a normal diet (10% fat) or the high-fat diet during pregnancy only. Female mice from the high-fat diet group and the 2 control groups were mated with male mice that were fed a normal diet. At E12.5, embryonic hearts were harvested to determine the levels of lipid peroxides and superoxide, endoplasmic reticulum stress markers, cleaved caspase 3 and 8, and apoptosis. E17.5 embryonic hearts were harvested for the detection of congenital heart defect formation using India ink vessel patterning and histological examination. RESULTS Maternal type 2 diabetes mellitus significantly induced ventricular septal defects and persistent truncus arteriosus in the developing heart, along with increasing oxidative stress markers, including superoxide and lipid peroxidation; endoplasmic reticulum stress markers, including protein levels of phosphorylated-protein kinase RNA-like endoplasmic reticulum kinase, phosphorylated-IRE1α, phosphorylated-eIF2α, C/EBP homologous protein, and binding immunoglobulin protein; endoplasmic reticulum chaperone gene expression; and XBP1 messenger RNA splicing, as well as increased cleaved caspase 3 and 8 in embryonic hearts. Furthermore, maternal type 2 diabetes mellitus triggered excessive apoptosis in ventricular myocardium, endocardial cushion, and outflow tract of the embryonic heart. CONCLUSION Similar to those observations in type 1 diabetic embryopathy, maternal type 2 diabetes mellitus causes heart defects in the developing embryo manifested with oxidative stress, endoplasmic reticulum stress, and excessive apoptosis in heart cells.

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Section: Commentmentioning

confidence: 99%

Type 2 diabetes mellitus induces congenital heart defects in murine embryos by increasing oxidative stress, endoplasmic reticulum stress, and apoptosis

Reece

Zhong

et al. 2016

American Journal of Obstetrics and Gynecology

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“…In pregnancy, it is generally advised that treatment decisions be based on mutation status of the fetus, due to risk of fetal macrosomia in cases where the fetus is unaffected, though there does not appear to be long-term metabolic consequences for unaffected fetuses [12]. GCK-MODY may be a risk factor for pregnancy complications [13]. Outside of pregnancy, treatment can be discontinued in most individuals following genetic diagnosis to confirm GCK-MODY.…”

Section: Introductionmentioning

confidence: 99%

GCK-MODY in the US National Monogenic Diabetes Registry: frequently misdiagnosed and unnecessarily treated

et al. 2016

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Aims GCK-MODY leads to mildly elevated blood glucose typically not requiring therapy. It has been described in all ethnicities, but mainly in Caucasian Europeans. Here we describe our United States cohort of GCK-MODY. Methods We examined the rates of detection of heterozygous mutations in the GCK gene in individuals referred to the US Monogenic Diabetes Registry with a phenotype consistent with GCK-MODY. We also assessed referral patterns, treatment, and demography, including ethnicity, of the cohort. Results Deleterious heterozygous GCK mutations were found in 54.7% of Registry probands selected for GCK sequencing for this study. Forty-nine percent were previously unnecessarily treated with glucose-lowering agents, causing hypoglycemia and other adverse effects in some of the subjects. The proportion of probands found to have a GCK mutation through research based testing was similar across each ethnic group. However, together African American, Latino and Asian subjects represented only 20.5% of screened probands and 17.2% of those with GCK-MODY, despite higher overall diabetes prevalence in these groups. Conclusions Our data show a high detection rate of GCK-MODY is possible based on clinical phenotype, and that prior to genetic diagnosis, a large percentage are inappropriately treated with glucose-lowering therapies. We also find low minority representation in our Registry, which may be due to disparities in diagnostic diabetes genetic testing, and is an area needing further investigation.

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“…Different types of insulin are used clinically to control glucose, and insulin analogues are often used to treat type 1 or 2 diabetic patients 147 . For women whose blood glucose is poorly controlled by daily insulin injections, subcutaneous insulin pumps might be useful in such settings 148,149 .…”

Section: Future Perspectives and Clinical Relevancementioning

confidence: 99%

“…For women whose blood glucose is poorly controlled by daily insulin injections, subcutaneous insulin pumps might be useful in such settings 148,149 . Although insulin and insulin analogues have been shown to improve HbA1c, with less risk of hypoglycaemia and with little or no adverse effects on the developing fetus 147,150–152 , use of anti-diabetic therapeutics alone has not completely eliminated the incidence of hyperglycemia-induced birth defects 153 .…”

Section: Future Perspectives and Clinical Relevancementioning

confidence: 99%

New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects

Dong

Reece

Xue

et al. 2016

American Journal of Obstetrics and Gynecology

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Maternal diabetes is a significant risk factor for structural birth defects, including congenital heart defects and neural tube defects (NTDs). With the rising prevalence of type 2 diabetes and obesity in women of childbearing age, diabetes-induced birth defects have become an increasingly significant public health problem. Maternal diabetes in vivo and high glucose in vitro induce yolk sac injuries by damaging the morphology of cells and altering the dynamics of organelles. The yolk sac vascular system is the first system to develop during embryogenesis, therefore, it is the most sensitive to hyperglycemia. The consequences of yolk sac injuries include impairment of nutrient transportation due to vasculopathy. Although the functional relationship between yolk sac vasculopathy and structural birth defects has not yet been established, a recent study reveals that the quality of yolk sac vasculature is inversely related to embryonic malformation rates. Studies in animal models have uncovered key molecular intermediates of diabetic yolk sac vasculopathy, including hypoxia-inducible factor-1α (HIF-1α), apoptosis signal-regulating kinase 1 (ASK1) and its inhibitor thioredoxin-1 (Trx), c-Jun-N-terminal kinases (JNK), nitric oxide (NO) and nitric oxide synthase (NOS). Yolk sac vasculopathy is also associated with abnormalities in arachidonic acid and myo-inositol. Dietary supplementation with fatty acids that restore lipid levels in the yolk sac lead to reduction in diabetes-induced malformations. Although the role of the human yolk in embryogenesis is less extensive than in rodents, nevertheless, human embryonic vasculogenesis is negatively affected by maternal diabetes. Mechanistic studies have identified potential therapeutic targets for future intervention against yolk sac vasculopathy, birth defects, and other complications associated with diabetic pregnancies.

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The clinical management of hyperglycemia in pregnancy complicated by maturity-onset diabetes of the young

Cited by 41 publications

References 27 publications

Type 2 diabetes mellitus induces congenital heart defects in murine embryos by increasing oxidative stress, endoplasmic reticulum stress, and apoptosis

Type 2 diabetes mellitus induces congenital heart defects in murine embryos by increasing oxidative stress, endoplasmic reticulum stress, and apoptosis

GCK-MODY in the US National Monogenic Diabetes Registry: frequently misdiagnosed and unnecessarily treated

New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects

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